Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts

人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学

• 批准号: 10359325
• 负责人: John Pierce Wise
• 金额: $ 10.51万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359325
• 关键词: Address; Affect; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Automobile Driving; BRCA2 gene; Beets; Betaine; Biological Markers; Breast Cancer Cell; Cancer Etiology; Carcinogens; Cell Death; Cells; Cessation of life; Chromium Compounds; Chromosomal Instability; DNA; DNA Double Strand Break; Data; Double Strand Break Repair; Endothelial Cells; Environment; Epithelial Cells; Event; Exposure to; Fibroblasts; Filament; Food; Funding; Goals; Hazardous Substances; Health Benefit; Heritability; Human; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Investments; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metals; Molecular; Mus; National Institute of Environmental Health Sciences; Natural Products; Neoplastic Cell Transformation; Nucleoproteins; Outcome; Particulate; Pathway interactions; Property; Proteins; Public Health; RAD51C gene; Rattus; Regulatory Pathway; Reporting; Research; Risk; Risk Assessment; Risk Management; Role; Signal Transduction; Structure of parenchyma of lung; Testing; Toxicology; Translating; Umbilical vein; United States; Work; Workplace; XRCC2 gene; anti-cancer; arm; cancer cell; carcinogenesis; carcinogenicity; chromium hexavalent ion; genotoxicity; homologous recombination; improved; in vivo; insight; neoplastic; neoplastic cell; novel strategies; parent grant; potential biomarker; prevent; response; targeted biomarker; therapeutic target; tumor; tumor progression

PROJECT SUMMARY OF THE FUNDED PARENT GRANT Lung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combating it is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major public health concern because exposure to it is common in the workplace and in the general environment. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. In particular, this work focuses on the particulate Cr(VI) compounds, because they are the most potent Cr(VI) carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells to evade DNA double strand break repair, which are hallmarks of human lung cancer. Thus, this research focuses on how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosome instability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts the effector arm of homologous recombination (HR repair), disrupting RAD51 nucleoprotein filament formation, loss of which can cause chromosome instability. Therefore, the goal of this research is to characterize this impact on HR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is: particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivating HR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test this hypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 to disrupt RAD51 nucleoprotein filament formation in human lung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation in human lung cells neoplastically transformed by Cr(VI), and the protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impact of Cr(VI) on protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in the lungs and lung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of the interactions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the first characterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers. Results will also show which changes are transient and depend on exposure and which changes persist in cells that escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1) An understanding of Cr(VI)’s carcinogenic mechanism; 2) Essential information to better assess exposure risk to particulates; and 3) A mechanistic approach for further study of Cr(VI), other metals and lung cancer in general.

资助的家长补助金项目摘要 肺癌仍然是美国癌症死亡的主要原因，这是对抗肺癌的关键策略之一 六价铬[Cr(VI)]是主要公众肺癌致癌物。 健康问题，因为在我们的研究中，接触它在工作场所和一般环境中很常见。 重点研究目前未知的 Cr(VI) 诱导致癌机制。 特别是，这项工作重点关注颗粒 Cr(VI) 化合物，因为它们是最有效的 Cr(VI) 最近的研究表明颗粒 Cr(VI) 会导致染色体不稳定并导致细胞 逃避DNA双链断裂修复，这是人类肺癌的标志，因此，本研究的重点是。 关于颗粒 Cr(VI) 如何诱导细胞逃避导致染色体的 DNA 双链断裂修复 我们的数据显示，长期接触颗粒 Cr(VI) 特别会影响 同源重组效应臂（HR 修复），破坏 RAD51 核蛋白丝形成、丢失 因此，本研究的目标是表征这种对染色体的影响。 为了理解 HR 修复和潜在的变化，我们的假设是： 颗粒 Cr(VI) 破坏 RAD51 核蛋白丝形成失活的潜在机制 Cr(VI) 诱导的 DNA 断裂的 HR 修复导致 CI​​N 和肿瘤转化。我们将对此进行测试。 通过三个相互关联的具体目标的假设将确定 Cr(VI) 如何影响 BRCA2、DSS1、 RAD51B、RAD51C、RAD51D、RPA 和 XRCC2 可破坏人类 RAD51 核蛋白丝的形成 目标 2 确定 RAD51 细丝形成中断的持久性和细胞遗传力。 Cr(VI)肿瘤转化的人肺细胞，以及BRCA2、DSS1、RAD51B、 人类 Cr(VI) 工人肺部肿瘤中的 RAD51C、RAD51D、RPA 和 XRCC2 确定了影响。 Cr(VI) 对肺中 BRCA2、DSS1、RAD51B、RAD51C、RAD51D、RPA 和 XRCC2 蛋白水平的影响 Cr(VI) 暴露动物的肺部肿瘤的结果将导致有关详细信息的第一份报告。 Cr(VI) 与 HR 修复效应臂在细胞和分子水平上的相互作用以及第一个 肿瘤结局中这些方面的特征，包括接触六价铬工人的肿瘤。 结果还将显示哪些变化是短暂的并且取决于暴露，哪些变化在细胞中持续存在 这项研究意义重大，因为它提供了：1) 了解 Cr(VI) 的致癌机制；2) 更好地评估暴露风险的基本信息； 颗粒物；3) 进一步研究 Cr(VI)、其他金属和肺癌的机制方法。

项目成果

Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells.

长期接触铬酸盐颗粒会导致人肺细胞中心体过早分离和中心粒脱离。

• DOI: 10.1093/toxsci/kfv146
• 发表时间: 2015-10-01
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: J. Martino;Amie L. Holmes;Hong Xie;S. Wise;J. Wise
• 通讯作者: J. Wise

The Novel Evolution of the Sperm Whale Genome.

抹香鲸基因组的新进化。

• 发表时间: 2017-12-01
• 作者: Warren, Wesley C;Kuderna, Lukas;Alexander, Alana;Catchen, Julian;Pérez;López;Quesada, Víctor;Minx, Patrick;Tomlinson, Chad;Montague, Michael J;Farias, Fabiana H G;Walter, Ronald B;Marques;Glenn, Travis
• 通讯作者: Glenn, Travis

A Case Study for Teaching Toxicology: Using Whales as an Indicator for Environmental Health.

毒理学教学案例研究：使用鲸鱼作为环境健康指标。

• 发表时间: 2022
• 作者: Rupprecht, Bryanna;Wise Sr, John Pierce;Reynolds, Mindy
• 通讯作者: Reynolds, Mindy

Mechanisms of metal-induced centrosome amplification.

金属诱导中心体扩增的机制。

• 发表时间: 2010-12
• 影响因子: 3.9
• 作者: Holmes, Amie L;Wise, John Pierce
• 通讯作者: Wise, John Pierce

Hexavalent chromium is cytotoxic and genotoxic to American alligator cells.

六价铬对美洲鳄细胞具有细胞毒性和基因毒性。

• DOI: 10.1016/j.aquatox.2015.12.004
• 发表时间: 2016-02
• 期刊: Aquatic toxicology
• 影响因子: 4.5
• 作者: Wise SS;Wise C;Xie H;Guillette LJ Jr;Zhu C;Wise JP Jr;Wise JP Sr
• 通讯作者: Wise JP Sr